ClinVar Miner

Submissions for variant NM_025114.3(CEP290):c.6628C>T (p.Arg2210Cys) (rs374852145)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483414 SCV000568654 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing The R2210C variant in the CEP290 gene has been reported previously as a single heterozygous variant in a fetus with posterior encephalocele, abnormal posterior fossa, multicystic dysplastic kidneys, club feet, shortened limbs and ambiguous genitalia who also harbored a splice site variant in the B9D1 gene; the R2201C variant was classified as a likely pathogenic variant by the authors but additional detailed evidence supporting the pathogenicity was not specified (Hopp et al., 2011). The R2210C variant was not observed at any significant frequency in approximately 5800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2210C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the information currently available, we interpret R2210C as a variant of uncertain significance.
Invitae RCV000636992 SCV000758440 uncertain significance Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2017-09-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2210 of the CEP290 protein (p.Arg2210Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs374852145, ExAC 0.03%). This variant has been reported an individual affected with Meckel syndrome (PMID: 21493627), however two pathogenic variants in the B9D1 gene were also identified in that individual. ClinVar contains an entry for this variant (Variation ID: 420090). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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